A Highly Step‐Economical Synthesis of Dictyostatin

Conformation–activity relationships of polyketide natural products

“…52 Given the failure of discodermolide in clinical trials, attention has turned towards dictyostatin as a potential alternative. To date there have been eight published total syntheses of 18 , 53 with the Paterson 54 and Curran 55 groups additionally providing a wealth of analogues for testing. Although most of these analogues have exhibited diminished activity, their cumulative biological results have provided a comprehensive picture of dictyostatin’s structure-activity relationships.…”

“…The low isolation yield of Pettit and co-workers initially led to an incomplete stereochemical assignment, leaving the structure of dictyostatin unclear until its re-isolation in 2003 52 and subsequent work by Paterson and co-workers in 2004. 58 By utilizing both homonuclear ( 3 J H,H ) and heteronuclear ( 2,3 J C,H ) coupling constants in combination with NOESY experiments they were able to determine the complete relative stereochemistry, which was later confirmed as the absolute configuration through the concurrent synthetic efforts of the Paterson 53a and Curran 53b groups. The Paterson group further combined this NMR data with Monte Carlo conformational searches to propose a pair of interconverting atropisomers, wherein the lactone adopts either a C1-C2 s-trans or s-cis orientation.…”

Enantioselective Hydroformylation of 1-Alkenes with Commercial Ph-BPE Ligand

“…However, the use of AHF in the context of total synthesis is not common, perhaps due in part to limited availability of requisite ligands. 6 …”

Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

“…The requisite bromide cross-coupling partner was prepared as outlined in Figure 4b. Based on our demonstration of a one-pot hydro-formylation-crotylation reaction with 2-vinyl-1,3-dioxolane in our dictyostatin synthesis, 23 we envisioned that the C(12) and C(13) stereocenters could be established using this strategy and employed ( S , S )-Ph-BPE as the ligand for the asymmetric hydroformylation following Morken’s demonstration that this ligand leads to improved levels of regioselectivity. 24 Using these conditions and our one-pot asymmetric allylation method with diaminophenol 14 , 25 we isolated 15 (≥20:1 dr ) in 81% yield (and recovered 14 in 92% yield).…”

“…The result is a fragment coupling and end game sequence that couples the two fragments, establishes three stereocenters, and removes the two protecting groups in just two steps. The step-economy as well as the practicability of the synthesis also derive in part from the asymmetric hydroformylation-allylation/crotylation of commercially available vinyl acetals, 23 an approach which obviates most of the protecting group and oxidation state manipulations that have historically reduced step-economy in non-aromatic polyketide natural product syntheses, delivers polypropionate stereodiads and stereotriads in one or two steps, and which was used to establish five of the 13 asymmetric centers in zincophorin methyl ester in just three total steps. The extraordinary power of this methodology is most clearly evident in the development of a synthesis of ketone 11 comprising five stereocenters in just six steps.…”